DESCRIPTION: The overall objective of the studies proposed herein is the development of animal models that will then be used to examine the genetic basis of exocrine pancreatic cancer. Pancreatic cancer is the fourth most lethal cancer in the human population. It is typically diagnosed at an inoperable stage so that long term patient survival is exceptionally low. Increased understanding of the molecular pathogenesis of this disease may form a necessary foundation for attempts to reverse the poor prognosis. The development of transgenic animal technology has permitted the establishment of models of complex genetic diseases like cancer for which the effects of selected genetic alterations can be correlated with specific pathophysio-logical consequences in vivo. However, the transgenic approach has had several technical limitations, including lack of inducible systems for targeting transgene expression and the down regulation of transgene transcriptional regulatory elements in certain experimental contexts, such as neoplastic progression. The studies proposed in the application employ two recent advances in transgenic methodology, the tetracycline responsive system and the cre/lox recombinase system, to create models of exocrine pancreatic neoplasia that avoid the limitation described above and that should more closely reflect the etiological mechanisms believed to cause this disease in the human population. These models are then used to characterize the pathogenetic basis of the disease. The specific aims are: (1) establish animal models of ductal neoplasia that reproduce the ductal origin of this cancer in humans; (2) characterize the pathogenic effects of genetic alterations that have been associated with the development and progression of exocrine pancreatic cancer in humans; and (3) determine, between species, the comparative pathogenicity of cancer- related genetic alterations. The final aim generation of transgenic rat models of exocrine pancreatic cancer, addresses the fact that we must continually reason by analogy from one species to another when using animal models to study human disease. The goal of this aim is to directly compare, between species, the pathophysiological responses to identical, precisely defined genetic alterations.